Bothersome lower urinary tract symptoms (LUTS) due to BPH are common and cause significant morbidity among older men. The long-term objective of this F30 fellowship project is improved understanding of estrogen receptor (ER) action in BPH and development of novel therapeutic strategies to combat this common disease process. The proposed F30 fellowship project addresses important priorities in benign prostate disease research by using a translational mouse model system to study endocrine effects on the male lower urinary tract in the training and career development of a future physician-scientist working toward the MD and PhD degrees. The etiology of BPH has long been attributed to pathologic recapitulation of development induced by sex steroid hormones, but the underlying molecular mechanisms have not been elucidated. As men age, serum testosterone (T) decreases while estradiol (E2) increases, paralleling the development of BPH and LUTS. Treatment of male dogs with androgens and estrogens induces earlier onset and more extensive BPH, and male rats treated with T+E2 develop enlarged prostates and obstructive voiding. Preliminary studies show that male mice treated with T+E2, in physiologic concentrations that mimic the hormonal milieu of older men, develop prostatic ductal growth, urethral narrowing and voiding dysfunction. The proposed fellowship research will determine the estrogen receptor important for mediation of these effects in the prostate with genetic strategies: use of ER knockout mice and tissue-specific ER knockout mice to determine receptor subtype and the importance of stromal versus epithelial ERs in BPH. Pharmacologic strategies to determine the necessity of ER will involve treatment of mice with T and selective ER-agonists and the evaluation of prostate growth, ductal branching and clinical sequelae of BPH. Prevention of BPH development will be tested with experimental selective estrogen receptor modulators (SERMs) that target relevant ER subtypes and the clinically relevant SERMs Raloxifene and Fulvestrant. Raloxifene will also be studied as a potential therapeutic strategy in nude mice implanted with human BPH xenografts. The goal of this fellowship research will be to elucidate the ER underlying induction of these effects in this mouse model and evaluate SERMs as potential therapies for BPH.